Treatment results of human hepatoblastoma (HB) have been improved remarkably during recent years, mainly through the establishment of integrated regimens controlled and coordinated by multicentric treatment studies. Today, neoadjuvant and adjuvant chemotherapy is combined with surgical resection of the tumors. The main therapeutic goal is a complete surgical removal of tumor masses, which is also essential for the survival of the patients. Despite improved overall survival rates, treatment results of advanced tumors are still far from being satisfying. Multidrug resistance has been identified as a major factor responsible for the bad prognosis of children suffering from advanced staged hepatoblastoma. During recent years investigations focused on factors contributing to drug resistance in hepatoblastoma and on possible approaches towards overcoming this therapeutical challenge. Alternative approaches that are currently evaluated in experimental and clinical settings comprise new cytotoxic agents, chemosensitizers, gene directed applications but also surgical techniques and an expansion of indication for liver transplantation.